Glycogen Storage Disease IV (GDS IV) of the Norwegian Forest Cat in Europe.

History.

This hereditary disease has been described for the first time in United States 15 years ago and was characterized by strange deaths after neuromuscular troubles concerning only related young cats. At this time Professor John Fyfe succeeded in proving that there was a genetic cause because of the narrow inbreeding for starting American NFC lines.
The mutation has been sequenced by J. Fyfe, a genetic test has been developed and has been available since 96.

Though the first cases have only been reported two years ago in Germany, the disease is likely to to increase because until now the ancestors of American NFC stayed in Europe. They unfortunately contribute to widespread the mutation in the NFC European population. As nobody (breeders and veterinarians) really knew about this problem and that almost all cases are just represented by neonatal death, the situation was unknown in Europe.
In France GDS IV testing enables us to keep veterinarians informed of this disease and we have already found three young NFC which were likely to be affected by GDS IV according to their veterinarian’s memory.

Genetics.

As with all Mammals, cats have several pairs of chromosomes, which form part of their genetic information. Each chromosome is composed of several genes and all genes present different possible forms which are called alleles.
Each animal inherits a chromosome from his father and the other from his mother that is to say a paternal and a maternal allele. 
This allele is called recessive when it is present twice in the same animal. Otherwise it’s a dominant allele (or co-dominant when both alleles express themselves at the same time). GDS IV mutation is recessive to wild (or normal) allele.

Three different possibilities can be found.

• Both parents are healthy (they are homozygote for the normal allele), so their children will be healthy.
• If one is a carrier (heterozygote), we will get around 50% of carriers and 50% of healthy cats among their children. Unfortunately when an unknown carrier is always mated with healthy cats, he doesn’t show he carries the mutation and it’s disastrous when such a cat has many descendants.
• When two carriers are mated together we get 25% of ill cats, 50% of carriers and 25% of healthy cats.

Should I feel concerned by this story?

At least two different lines seem to be concerned by this problem. Unfortunately it could be three or four … We have no background history of this disease and we do not have enough data to confirm that only two novices were carriers.
However mutations are scarce events that is why we are currently searching for a relation between these lines, maybe a geographical or professional relation but researches are difficult because of novices.

What are the clinical signs of affected cats?

GDS IV pathogenic corresponds to a deficiency in glycogen stocking. Clinical signs are due to a chronic hypoglycaemia getting gradually worse. Consequently GDS IV is especially dominated by neuromuscular signs.  
 

• Most of affected kitten are still-born or die quickly after birth (in the first hours or days).
• There is another clinical form; this form is scarcer but more specific too. Some homozygote affected kittens grow normally until age of 5-7 months. But suddenly they stop their development and become weaker and weaker with the following clinical signs:
• High hyperthermia (over 40 degree Celsius). Corticosteroids are completely ineffective against this fever.
• Intermittent generalized body tremors getting permanent
• Intermittent listlessness and “bunny hopping”.
• Muscle weakness then muscle atrophy, fibrotic contractures of selected joints leading to difficulties for moving itself, eating … involving a lot of nursing for the owner.
• Tetraplegia
• The disease is inevitably lethal, often around age of 10 to 14 months. Such young adult die of hearth attack sometimes after coma. Nevertheless the owner often decides to euthanatize his pet because he seems to suffer a lot in the last months of life.

GDS IV diagnosis?

Different analyses can be undertaken: creatinine kinase (CK) activity increases (proving muscular lesions) and sometimes hepatic parameter ALT too.
Needle electromyography is informative but the only sure diagnosis needs genetic test. Two labs currently propose this test in Europe: Antagène in France, Lakoblin in Switzerland.
In the past they used histopathology or measured GBE activity (GBE is the deficient enzyme in GDS IV). 

What should we do?

Nowadays the genetic test enables us to detect not only affected cats but carriers which are the real problem and THE danger for the breed. 
Nobody can assure that his lines are healthy. Indeed still-born babies are quite usual in breeding whereas the neuromuscular form was still completely unknown to most of European breeders and veterinarians until the beginning of this year.

Of course we are unlikely to find GDS IV allele in a cattery which has never had any problems in his lines despite lots of inbreeding. However it cannot be excluded, GDS IV problems can sometimes take up to ten years before becoming obvious. For example we find GDS IV in unexpected lines in France and Germany. 

By disregarding this problem, the carrier frequency is going to increase as soon as the mutation meets a well-known line.
We currently know that well-known North-European catteries have already had (or always had?) carriers because some exported kittens have been tested positive.
Besides I must add that we have a doubt too for a Skogkatt of the Year who bred at least two suspected cats in two different litters.

Nevertheless this disease is sublethal: all affected cats die before having the opportunity to have descendants and to spread the mutation. Consequently the disease frequency should remain constant which explains why we “just” have 8% of carriers in France.

Well you are likely to wonder why we advise you to test your cats if the frequency doesn’t increase. In  answer I invite you to imagine  an owner’s ordeal when he buys an affected kitten who develops the first signs only two months later. Today we know the disease and we have ways of combatting it. 
Moreover each breeder has responsibilities towards the breed and its members and also towards other breeders too. History is an eternal beginning and the American situation in the nineties could be lived again elsewhere on earth, if a carrier were to be exported in a country where the NFC pool is limited. Now we know about it  we will be responsible for such problems.

Of course every breeders will still have still-born kittens … I don’t want you to worry needlessly but just to ask you several questions before saying that you are not concerned.
Testing a cat today corresponds to several cats that we won’t need to be tested in years to come.

I was the first to think that we could ignore this story. However we found around 6% of carriers in France and 8% in France with Germany. This is quite important for a disease that was not known at the beginning of the year.

What should I do if one of my cats is a carrier?

• This cat should be neutered and all his breeding descendants should be tested.
• However if the concerned cat is very important for your breeding plans and is nearly perfect he can be mated with healthy cats. All breeding kittens have to be tested and the carriers reserved as pets. Before being sold such kittens should be neutered and get a chip.    
• If you don’t have any carriers and if you want to buy a new cat require the breeder to sell you a healthy cat. Do the same when you accept to do strange covering.

Amber and Glycogen Storage Disease?

The two first European affected cats were amber and enabled us to unearth a problem we have already heard about without feeling really concerned.
However GDS IV does not concern only amber cats! Unfortunately some amber ancestors met GDS IV carriers and the inbreeding for fixing the colour selected in the same time GDS IV. Indeed GDS IV has been described for the first time in the United States but amber colour never appeared over there despite inbreeding.

Today GDS IV testing has been led in several amber German catteries.
If the first results seemed to be frightening the definitive results are rather good and there are only some carriers.
An appropriate selection will enable to forget GDS IV in several years. For avoiding the same problem in the future all introduced cats in these breeding plans have to be tested.

If you want to know more …

Articles

FYFE et al. (2007)
A complex rearrangement in GBE1 causes both perinatal hypoglycaemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats, Mol Genet Metab. 90, 4, 383-92.

FYFE et al. (1992)
Glycogen storage disease type IV: inherited deficiency of branching enzyme activity in cats., Pediatr Res. 32, 6, 719-25.

FYFE (1995)
Glycogen storage disease in cats, J Am Vet Med Assoc. 206, 3, 286.

GASCHEN et al.
In Congenital feline myopathies, Glycogen Storage disease type IV, 360-361

Web

http://ourworld.compuserve.com/homepages/L_P_SWEPSTON/GSD.htm

http://www.antagene.com/index.php?page_id=214&rubrique_id=126&coderub1=3&coderub2=0&coderub3=7&langue=L1&menu= (pour le dépistage)

http://www.winterfyre.com/testing/

http://w3.vet.upenn.edu/research/centers/penngen/services/deublerlab/gsd4.html

http://gsd4.de.vu/ (German)

Written by Marc PETERSCHMITT, veterinarian.
Corrected by Vera Nielsen Taylor.